Certain pyridyl malonates

ABSTRACT

This disclosure relates to phenyl-pyridyl-alkanoic acids and derivatives which possess anti-inflammatory, analgesic and antipyretic activity, and which reduce the concentration of fibrinogen, cholesterol and triglycerides in blood. It also relates to processes for making said compounds, to pharmaceutical compositions, and to methods of treatment involving said compounds. A representative of said compounds is 6-(4chlorophenyl)-2-methylpyrid-3-ylacetic acid.

' [22] Filed:

I United States Patent Doyle et al.

[ June 27, 1972 [54] CERTAIN PYRIDYL MALONATES [72] Inventors: PeterDoyle; Joseph Gilbert Stacey, both of Macclesfield, England ImperialChemical Industries Limited, London, England Aug. 5, 1970 [21] Appl.N0.: 61,404

Related U.S. Application Data [62] Division of Ser. No. 682,593, Nov.13, 1967, Pat. No.

[73] Assignee:

[58] Field of Search ..260/295 R, 295.5 R

[56] References Cited UNITED STATES PATENTS 3,381,015 4/1968 Shen et al...260/295 3,396,224 8/1968 Van Heyningen ..260/295 Primary ExaminerAlanL. Rotman A tt0rney--Cushman, Darby & Cushman [5 7] ABSTRACT Thisdisclosure relates to phenyl-pyridyl-alkanoic acids and derivativeswhich possess anti-inflammatory, analgesic and antipyretic activity, andwhich reduce the concentration of fibrinogen, cholesterol andtriglycerides in blood. it also relates to processes for making saidcompounds, to pharmaceu-' tical compositions, and to methods oftreatment involving said compounds. A representative of said compoundsis 6-(4- chlorophenyl)-2-methylpyrid-3-ylacetic acid.

3 Claims, No Drawings CERTAIN PYRIDYL MALONATES This is a division ofour copending application, Ser. No. 682,593, filed Nov. 13, l967whichhas matured into US. Pat. No. 3,546,237 granted on Dec. 8, 1970.

This invention relates to heterocyclic compounds and more particularlyit relates to new pyridine derivatives which have amt-inflammatory,analgesic and antipyretic activity, and which reduce the concentrationof fibrinogen and of cholesterol and/or trigylcerides in blood and whichmay therefore be useful in the treatment or prophylaxis of coronaryartery disease and atherosclerosis.

According to the invention we provide pyridine derivatives of theformula:-

Y CR R R wherein X stands for hydrogen, an alkyl or alkoxy radical ofnot more than 3 carbon atoms, or a halogen atom, and Y stands for aphenyl radical optionally substituted by not'more than two halogenatoms, and R stands for hydrogen or an alkyl radical of not more than 3carbon atoms, and R stands for hydrogen, an alkyl radical of not morethan 3 carbon atoms, or an alkoxycarbonyl radical of not more than 6carbon atoms, and R stands for a radical of the formula CONl-l or -CORwherein R stands for hydrogen or an alkyl radical of not more thancarbon atoms, and wherein the Y and CRR R radicals are linked tonon-adjacent carbon atoms of the pyridinenucleus, and salts thereof.

It is to be understood that the above definition does not includecompounds wherein the radicals represented by Y and CRR R occupyadjacent positions on the pyridine nucleus, and similarly thedefinitions of various intermediates given below do not includecompounds wherein the radicals which correspond to Y and -CRR R occupyadjacent positions on the pyridine nucleus.

As a suitable value for X there may be mentioned, for example, hydrogen,a methyl or methoxy radical, or a chlorine or bromine atom.

As a suitable value for the halogen atom(s) which may optionally bepresent in the radical Y there may be mentioned fluorine, chlorine andbromine atoms. Compounds wherein Y contains one or two halogensubstituents comprise a preferred embodiment of this invention because,generally speaking, they are more active than the correspondingunsubstituted phenyl derivatives. 5

As a suitable value for R or R when it stands for an alkyl radical theremay be mentioned,fo'r example, a methyl radical. As a suitable value forR when it stands for an alkoxycarbonyl radical there may be mentionedthe methoxycarbonyl or ethoxycarbonyl radical. 7

As a suitable value for R when it stands for an alkyl radical there maybe mentioned, for example the methyl or ethyl radical.

As suitable salts in the case where CRR R stands for an ester or amidegroup there may be mentioned pharmaceutically acceptable acid-additionsalts, for example hydrochlorides, hydrobromides, sulphates orphosphates. In the case where R stands for the carboxy radical (CO H),suitable salts are salts with alkali metals or alkaline earth metals,-aluminum salts, and salts with pharmaceutically acceptable organicbases.

Preferred pyridine derivatives of the invention are 6-(4-chlorophenyl)-2methylpyrid-3-ylacetic acid, a-[6-(4chlorophenyl)-2methylpyrid-3-yl]propionic acid, dimethyl5-(4-chlorophenyl)pyrid-2-ylmalonate, sodium 5-(4-chlorophenyl)pyrid-Z-ylacetate, sodium 3-(4-chlorophenyl)-2methoxypyrid-6-ylacetate, and sodium2-(4-chlorophenyl)pyrid-4-ylacetate, and of these the first two areparticularly preferred.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

Y CR R CONH wherein X, Y, R and R have the meanings stated above, andsalts thereof, which comprises the hydrolysis of a pyridine derivativeof the formula:

wherein X, Y R and R have the meanings stated above.

The hydrolysis is carried out in the presence of water, and as asuitable hydrolytic agent there may be mentioned, for example, an acid,for example an inorganic acid, for example sulphuric acid, or aninorganic base, for example an alkali metal hydroxide, for examplepotassium hydroxide. A diluent, for example ethanol, may optionally bepresent. The hydrolysis may be accelerated or completed by theapplication of heat.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

wherein X, Y R and R have the meanings stated above, and salts thereof,which comprises the hydrolysis of 'a pyridine derivative of the formulaY CR R -R wherein X, Y, R and R have the meanings stated above, and Rstands for the cyano (CN) or carbamoyl (CONH radical.

The hydrolysis is carried out in water, and an organic solvent, forexample ethanol, may optionally be present. As a suitable hydrolyticagent there may be mentioned, for example, an inorganic base, forexample an alkali metal hydroxide, for example sodium or potassiumhydroxide, or an acid, for example an inorganic acid, for examplehydrochloric acid.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

Y cram-002R wherein X, Y, R and R have the meanings stated above, and Rstands for an alkyl radical of not more than five carbon atoms, andsalts thereof, which comprises the esterification of a pyridinederivative of the formula:

Y ca m-coin wherein X, Y, R and R have the meanings stated above.

The esterification may be carried out by interaction of the carboxylicacid with a compound of the formula ROH, wherein R stands for an alkylradical of not more than five carbon atoms, and an inorganic acid, forexample sulphuric acid, or dicyclohexylcarbodiimide. The reaction mayoptionally be carried out in an organic solvent, for example chloroform,and it may be accelerated or completed by the application of heat,Alternatively, the esterification may be carried out by the interactionof the carboxylic acid with the appropriate diazoalkane, for examplediazomethane, in an organic solvent, for example a mixture of methanoland ether. Alternatively, the esterification may be carried out by theinteraction of a metal salt of the appropriate carboxylic acid, forexample an alkali metal salt, with a compound of the formula RHal,wherein R stands for an alkyl radical of not more than five carbonatoms, and Hal stands for a halogen atom, for example a chlorine orbromine atom. The reaction may ptionally be carried out in an organicsolvent, for example dimethylformamide, and it may optionally beaccelerated or completed by the application of heat.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

wherein X, Y, R and R have the meanings stated above, and

R stands for an alkyl radical of not more than five carbon atoms, andsalts thereof, which comprises the interaction of a compound of theformula:

Y C R R -CN completed by the application of heat.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

wherein X, Y, R and R have the meanings stated above, and salts thereof,which comprises the hydrolysis of a compound of the formula:

wherein X, Y, R and R have the meanings stated above, and R stands foran alkyl, aralkyl or aryl radical.

As a suitable hydrolytic agent there may be mentioned, for example, analkali metal hydroxide, for example sodium hydroxide. The hydrolysis iscarried out in the presence of water, and one or more organic solvents,for example ethanol, may optionally also be present.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

Y CR 021102 and salts thereof, which comprises the interaction of sodiumor potassium or a hydride, amide or alkoxide thereof, with a carbonateof the formula CO.(OR) wherein R has the meaning stated above, and acompound of the formula:

Y ClI R wherein X, Y and R have the meanings stated above.

The reaction may be carried out in an excess of the appropriatecarbonate, and the appropriate alkanol, for example methanol, mayoptionally be present. The reaction may be accelerated or completed bythe application of heat. it is to be understood that in a case where Xin the starting material stands for a halogen atom, for example abromine atom, the last-named process can result in the production of theappropriate compound wherein X stands for the alkoxy radicalcorresponding to the carbonate used.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

CHR COzIl wherein X, Y and R have the meanings stated above, R

stands for an alkyl radical of not more than five carbon atoms. and Rstands for the cyano radical -CN) or an alkoxycarbonyl radical of notmore than six carbon atoms, with an inorganic base or inorganic acid inthe presence of water and under the influence of heat.

As a suitable inorganic base there may be mentioned, for example, analkali metal hydroxide, and as a suitable inorganic acid there may bementioned, for example, hydrochloric acid. The reaction may be carriedout in the presence of an organic solvent, for example'methanol.

According to a further feature of the invention we provide a process forthe manufacture of pyridine'derivatives of the formula:

wherein X, Y, R and R have the meanings stated above.

The alkylation process can result in the introduction of one alkylradical (e.g., in the product R stands for alkyl and R stands foralkoxycarbonyl), or in the'introduction of two alkyl I radicals (i.e.,in the product R and R stand for alkyl). The alkylation may be carriedout by reacting an alkali metal derivative, for example the sodiumderivative, of the appropriate pyridine derivative with an alkyl halideof not more than three carbon atoms, for example methyl iodide. Thereaction may be carried out in the presence of an organic solvent, forexample dimethylforrnamide.

According to a further feature of the invention we provide a process forthe manufacture of pyridine derivatives of the formula:

CaH CR R R wherein X, R, R and R have the meanings stated above, whichcomprises the interaction of a compound of the formula:

Y OR R R wherein X, R, R and R have the meanings stated above, and Ystands for a phenyl radical bearing not more than two halogen atoms,with hydrogen in the presence of a hydrogenation catalyst.

As a suitable hydrogenation catalyst there may be mentioned, forexample, a palladium-on-carbon catalyst. The reaction may be carried outin the presence of an organic solvent, for example ethanol.

It is to be understood that the compounds used as starting materials inthe processes described hereinbefore may all be obtained by generalprocedures which are well known in the art, as is illustrated in theexamples.

According to a further feature of the invention we providepharmaceutical compositions comprising at least one pyridine derivativeof the formula:

Y O FJR R wherein X, Y, R, R and R have the meanings stated above, or asalt thereof, and a non-toxic, pharmaceutically acceptable diluent orcarrier.

The pharmaceutical compositions may, for example, be in the form oftablets, pills, capsules, suppositories, non-sterile aqueous ornon-aqueous solutions or suspensions, sterile injectable aqueous ornon-aqueous solutions or suspensions, creams, lotions, or ointments.These compositions may be obtained in conventional manner usingconventional excipients. The compositions may optionally contain, inaddition to at least one of the pyridine derivatives which characterizethis invention, at least one known agent having anti-inflammatory and/oranalgesic activity, for example aspirin, paracetamol, codeine,chloroquine, phenylbutazone, oxyphenbutazone, idomethacin, mefenamicacid, flufenamic acid, ibufenac, or an anti-inflammatory steroid, forexample prednisolone. Those compositions intended for oraladministration may, in addition, optionally contain at least oneanti-cholinergic agent, for example homatropine methyl bromide, and/oran antacid, for example aluminum hydroxide. Those compositions designedfor topical application may, in addition, optionally contain avasodilating agent, for example tolazoline, or a vasoconstricting agent,for example adrenaline; a local anesthetic, for example amethocaine, ora counter-irritant, for example capsicum; and/or at least one agentchosen from the following classes of substances: anti-bacterial agents,which includes sulphonamides and antibiotics having antibacterialaction, for example neomycin; anti-fungal agents, for examplehydroxyquinoline; anti-histaminic agents, for example promethazine; andrubefacient agents, for example methyl nicotinate.

The invention is illustrated but not limited by the following examples:

EXAMPLE 1 6-(4-Chlorophenyl)-3-cyanomethyl-Z-methylpyridine (0.25g.) wasdissolved in 96 percent sulphuric acid (3.6g) and the resulting clearsolution was stirred for 4 hours at ambient temperature. The solutionwas then added to a mixture of concentrated ammonium hydroxide (4.4g.density 0.88) and ice-water (15g), The mixture was filtered and thesolid residue was crystallized from a mixture of isopropanol andmethanol. There was thus obtained 6-(4-chlorophenyl )-2-methylpyrid-3-ylacetamide, m.p.2 l 32 1 5 C.

The cyanomethyl compound used as starting material was obtained asfollows:

A solution of ethyl 6-(4-chlorophenyl)-2-methylpyridine-3- carboxylate20g.) in anhydrous ether (500ml.) was added to a stirred suspension oflithium aluminum hydride (4.9g.) in ether at such a rate that a gentlereflux was maintained. After 2 hours, the ethereal suspension was cooledand water (5ml.) was cautiously added, followed by 50 percent aqueoussodium hydroxide solution (3111].) added cautiously, followed by water(l7ml.). The suspension was stirred for 0.5 hour, dried over anhydrousmagnesium sulphate, filtered, and the solvent was evaporated in vacuo.There was thus obtained 6-(4-chlorophenyl)-3-hydroxymethyl-2-methyl-pyridine which was sufficientlypure for use in the next stage. A sample crystallized from carbontetrachloride had m.p.l l3l 15 C.

Thionyl chloride (1.6ml.) was added dropwise to a stirred solution of6-(4-chlorophenyl)-3-hydroxymethyl-Z-methylpyridine (2.58g.) inanhydrous ethylene dichloride (50ml.), and the resulting mixture wasstirred vigorously to redissolve the precipitate obtained after fifteenminutes. The resulting clear solution was evaporated to dryness afterminutes and the residue was stirred with anhy rous benzene (50ml.) Themixture was filtered, washed well with benzene, and dried on the filter.There was thus obtained 3-chloromethyl-6-(4-chlorophenyl)-2-methylpyridine hydrochloride which was sufficiently purefor use in the next stage. A sample of the chloromethyl compoundcrystallized from isopropanol had m.p. l7ll72 C.

A solution of 3-chloromethyl-6-(4-chlorophenyl)-2-methylpyridinehydrochloride (27g.) and sodium cyanide 16.2g.) in methanol (ml.) wasstirredunder reflux in a nitrogen atmosphere for 2 hours. The resultingsuspension was cooled and then concentrated in vacuo. The residue wasthoroughly mixed with either (800ml) and water (100ml.). The organiclayer was separated from the mixture and concentrated to m]. underreduced pressure. The mixture was then passed through a columnconsisting of neutral alumina (Woelm grade 1; 500g), and the column wascontinuously eluted with ether until 500ml. of eluate had beencollected. The solvent was evaporated, and there was obtained a solidwhich was crystallized from a mixture of ethyl acetate and petroleumether (b.p.60-80 C.). There was thus obtained 6-(4-chlorophenyl)-3-cyanomethyl-Z-methylpyridine, m.p.102-l04 C.

EXAMPLE 2 A mixture of 6-(4-chlorophenyl)-3-cyanomethyl-2-methylpyridine(l9g.), sodium hydroxide (22.4g.), and ethanolwater (7:3; 220ml.) wasrefluxed for 3 hours. The solvents were evaporated in vacuo, the residuewas dissolved in water (300ml.), and the solution was washed with ether(330ml.). The aqueous solution was adjusted to pH 4 by the cautiousaddition of concentrated hydrochloric acid, and the resulting mixturewas filtered. The solid residue was crystallized from ethyl acetate andthere was thus obtained 6-( 4-chlorophenyl)- 2-methylpyrid-3-ylaceticacid, m.p.180l82 C.

EXAMPLE 3 EXAMPLE 4 A suspension of6-(4-chlorophenyl)-2-cyanomethylpridine (6g) in dry methanol (26ml.) wascooled to C. in an icebath. Concentrated sulphuric acid (l7g.) wasslowly added, and the resulting pale yellow solution was refluxed for 18hours. The reaction mixture was added to ice (l50g.), and the pH of thesolution was adjusted to 8 by means of concentrated ammonium hydroxide(density 0.88). The solution was extracted 3 times with ether lOOml.),and the solvent was then evaporated from the combined ethereal extracts.The residual solid was crystallized from petroleum ether (6080 C.), andthere was obtained methyl 6-(4-chlorophenyl)pyrid-2- ylacetate, m.p.4546C.

The cyanomethyl compound used as starting material was obtained asfollows:

A solution of 6-(4-chlorophenyl)-2-methylpyridine (21g) in chloroform(400ml.) was cooled to 0 C. in an ice-bath. m- Chloroperbenzoic acid(30.9g.) was slowly added in portions to the solution, and the solutionwas then kept at O4 C. for 24 hours. The chloroform solution was shakenwith 15 percent aqueous potassium carbonate solution (l50ml.), and solidpotassium carbonate was added to bring the pH of the aqueous layer to 9.The chloroform layer was separated from the mixture, and then dried, andthe solvent was evaporated. There was thus obtained impure6-(4-chlorophenyl)-2- methylpyridine N-oxide. This can be purified bycrystallization from petroleum ether (b.p.6080 C.), and it then has m.p.9294 C.

The impure N-oxide (25g.) was dissolved in acetyl chloride (ll2ml.) andthe mixture was refluxed for 6 hours. After evaporation of excess acetylchloride, the residual brown oil, which consisted mainly of2-acetoxymethyl-6-(4-chlorophenyl )pyridine hydrochloride and2-chloromethyl-6-(4- chlorophenyhpyridine hydrochloride, was dissolvedin methanol (350ml). A solution of sodium hydroxide (20g) in water (20g)was added, and the mixture was kept at ambient temperature for 2 hours.The methanol was evaporated in vacuo, and the residue was partitionedbetween ether and water. The ethereal layer was separated from themixture, and the other was evaporated. There was thus obtained a mixtureof 6-(4-chlorophenyl)-2-hydroxymethylpridine and 2-chloromethyl-6-(4-chlorophenyl)pyridine which was satisfactory for usein the next stage. To a solution of this mixture (22g) in dry ethylenedichloride (300ml.) there was slowly added thionyl chloride (1 lml.);the temperature of the reaction mixture not being allowed to exceed35-40 C. The suspension was stirred for 1.5 hours, and then filtered.There was thus obtained 2-chloromethyl-6-(4-chlorophenyl)- pyridinehydrochloride. Crystallization of this salt from isopropanol gave thecorresponding base, m.p.l -l 1 1 C.

2-Chloromethyl-6-(4-chlorophenyl)pyridine hydrochloride (l5g.) wasdissolved in water (l50ml.). Concentrated ammonium hydroxide (density0.88;' 4g.) was added to the solution, and the mixture was extractedthree times with chloroform. The combined chloroform extracts weredried, the solvent was evaporated, and there was obtained crystalline2-chloromethyl-6-(4-chlorophenyl)-pyridine. This solid was dissolved indry methanol (230ml), sodium cyanide (6.6g) was added, and the mixturewas refluxed in a nitrogen atmosphere for 10 hours. The reaction mixturewas cooled, the solvent was evaporated and the residue was partitionedbetween ether and water. The mixture was separated and solvent wasevaporated from the organic layer. The residual solid was dissolved inether (200ml), and the solution was passed through neutral alumina(Woelm, grade 1; 250g. The solvent was evaporated from the eluate, andthe residue was crystallized from a mixture of ethyl acetate andpetroleum ether (b.p.60-80 C.). There was thus obtained6-(4-chlor0phenyl )-2-cyanomethylpyridine, m.p.80-82 C.

EXAMPLE 5 Methyl 6-(4-chlorophenyl)pyrid-2-ylacetate (0.15g.) wasdissolved in a mixture of methanol lml.) and N-aqueous sodium hydroxide(lml.). The mixture was stirred for 20 hours at ambient temperature.After evaporation of the methanol, the aqueous solution was dilutedwithwater lml. cooled in ice, and glacial acetic acid was added dropwiseuntil precipitation was complete. The crystalline precipitate wasseparated by filtration, washed with distilled water, and crystallizedfrom a mixture of acetone and petroleum ether, (b.p.6080 C.) at or belowambient temperature. There was thus obtained 6-(4- chlorophenyl)pyrid-2-ylacetic acid, m.p. 98 1 00 C. (decomp.).

EXAMPLE 6 5-(4-Chlorophenyl)-3-cyanomethyl-2- methyl-pyridine (6.05g.)was boiled under reflux for 2 hours with a 10 percent solution ofpotassium hydroxide in 2:1 ethanolrwater (50ml.). The cooled solutionwas diluted with water (ca. l20ml.), and most of the ethanol wasdistilled off under reduced pressure. The aqueous solution was washedwith ether, treated with decolorizing carbon, filtered, and brought topH 6 by addition of acetic acid. The precipitated5-(4-chlorophenyl)-2-methylprid-3-ylacetic acid was crystallized frommethanol, and had a m.p. of 207209.C. (decomp.).

The 5-(4-chlorophenyl)3-cyanomethyl-2-methyl-pyridine used as startingmaterial was obtained as follows:

Phosphorus oxychloride l lOml.) was added dropwise to drydimethylformamide (146g) which was stirred, and kept below 30 C. bycooling in an ice-bath. 4-Chlorophenylacetic acid (68.2g.) was added,and the solution was stirred at 70 C. for 6 hours. It was cooled, andpoured carefully on to crushed ice (ca.400g.). The resultant aqueoussolution was cooled to below 10 C. in an ice-salt bath while the pH wasadjusted to 7 by addition of aqueous 40 percent sodium hydroxide. Solidpotassium carbonate (600g) was added, together with benzene (ca.250ml.), and more water as required to facilitate dissolution, and thewhole was stirred at 70 C. for 2 hours. The benzene was separated in thecold and combined with two further benzene extracts of the aqueouslayer. The benzene extracts were washed with water, dried over magnesiumsulphate, and evaporated to leave a brown oil, which solidified onstanding, and which was crystallized from carbon tetrachloride to givea-( 4-chlorophenyl )-B- dimethylaminopropenal of m.p. l l9121 C.

ot-( 4-Chlorophenyl )-B-dimethylaminopropenal dissolved in alcohol-freechloroform 100ml.), dropwise to a stirred solution of phosgene (50g) inchloroform (ml.) which was meanwhile cooled to below 10 C. The mixturewas stirred at ambient temperature for 1 hour, and then volatilematerial was distilled off under reduced pressure. The residual oil wasmixed with ether (ca. 250ml.) and water (ca. 300ml.), and the ethersolution was separated and combined with two further ethereal extractsof the aqueous layer. After being washed in turn with water, diluteaqueous sodium carbonate, and water again, the ether solution was driedover sodium sulphate, and evaporated to leaveB-chloroa-(4-chlorophenyl)propenal as an oil, which solidified oncooling and then had a m.p. of 38-42 C. It was unstable on storage andwas therefore used straight away for the next stage of the synthesiswithout further purification.

(62.7g.), was added B-Chloro-a-(4-chlorophenyl)propenal (44.0g.), ethylB- aminocrotonate (68.5g.) and cyclohexane (600ml) were boiled togetherunder reflux for 9 hours. A small amount of solid was removed byfiltration in the cold, and the solution was evaporated to dryness underreduced pressure. The residue was dissolved in dry ether, and anethanolic solution of hydrogen chloride was added slowly untilprecipitation was complete. The hydrochloride so obtained was collectedby filtration, and mixed with water containing sufficient potassiumhydroxide to give alkalinity. The base was extracted into ether, washedwith water, dried over sodium sulphate, and recovered by evaporation.Crystallization from 2:l ethanol: water gave ethyl5-(4-chlorophenyl)-2-methyl-pyridine-3-carboxylate of m.p. 7273 C.

Ethyl 5-(4-chlorophenyl)-2-methylpyridine 3-carboxylate (22.0g.) in dryether (200ml.) was added slowly to lithium aluminum hydride (3.8g.)stirred in dry ether (120ml.) at 5l0 C. The whole was stirred at ambienttemperature for 1 hour, and then cooled in an ice-water bath while water(200ml.) was added carefully. Ether was distilled off under reduced pressure, and the aqueous suspension was filtered to give a solid. This wastriturated with ethyl acetate until no more solid dissolved. The ethylacetate solution was dried over sodium sulphate and evaporated to leavea solid. This was crystallized from benzene to give5-(4-chlorophenyl)-3-hydroxymethyl-2- methylpyridine, m.p. l35-136 C.

Thionyl chloride (7.2ml.) in methylene dichloride (20ml.) was addeddropwise to a stirred suspension of 5-(4-chlorophenyl)-3-hydroxymethyl-Z-methyl-pyridine (15.4g.) in methylenedichloride (l35ml.), maintained at a temperature of 2025 C. Whenaddition was complete, the mixture was boiled under reflux for 30minutes, and was then evaporated to dryness under reduced pressure. Theresidue was treated with ice-water and sufficient potassium hydroxide togive a pH of 10. Solid was extracted into methylene dichloride, washedwith water, dried over sodium sulphate, and recovered by evaporation.Crystallization from cyclohexane gave3-chloromethyl-5-(4-chlorophenyl)-2-methylpyridine, m.p.128l29.5 C.

A mixture of 3-chloromethyl-5-(4-chlorophenyl)-2-methylpyridine l4.7g.)and potassium cyanide (4.55g.) in 2-ethoxyethanol (60ml.) and water(30ml) was boiled under reflux for 2 hours. Solid separated on cooling,and water (lml.) was added to complete the precipitation. The solid wascollected by filtration, washed with water, redissolved in benzenel50ml.), dried over sodium sulphate, treated with decolorizing carbon,and recovered by evaporation of the solvent. Crystallization from carbontetrachloride gave -(4- chlorophenyl)-3-cyan0methyI-Z-methylpyridine,m.p.l27-1 28 C.

EXAMPLE 7 2-Bromo-3-(4-chlorophenyl)-6-methylpyridine (22.5g.) was addedto a suspension of sodium hydride (23g. of 50 percent dispersion in oilwashed with petroleum ether before use) in dimethyl carbonate (lml.).The whole was heated and stirred under reflux for 20 hours in anatmosphere of nitrogen. The mixture was cooled, and methanol was addedto destroy residual sodium hydride, followed by water (200ml.). Theaqueous suspension was thoroughly extracted with ether, and the etherealextract was washed repeatedly with 5N- hydrochloric acid until3-(4-chlorophenyl)-2-methoxy-6- methylpyridine had been removed as shownby thin layer chromatography. Finally, the extract was washed withdilute aqueous sodium carbonate, then with water, dried over sodiumsulphate, treated with decolorizing carbon, and evaporated down to leavea solid which was crystallized from petroleum ether (b.p.60-80 C.) togive dimethyl 3-(4- chlorophenyl )-2-methoxypyrid--ylmalonate, m.p.82-85C.

The 2-bromo-3-(4-chlorophenyl)-6-methylpyridine used in the abovepreparation was obtained as follows:

a-(4-Chlorophenyl)-a-hydroxymethyleneacetonitrile (g.) and acetone (80g)were well mixed with polyphosphoric acid (1,000g.) and heated steadilyto about C., at which temperature a vigorous exothermic reaction set in.The reaction was allowed to proceed on its own, but heat was laterapplied as required to keep the temperature between 130 and C. for 30minutes. The cooled mixture was poured on to ice, and the aqueoussuspension was a stirred for 18 hours before filtration. The crudematerial was stirred with ethyl acetate and dilute aqueous potassiumhydroxide in sufiicient quantity to maintain alkalinity. The solid wascollected by filtration, and was washed well with water, ethyl acetate,and ether in turn. The 3-(4-chlorophenyl)-l,2-dihydro-6-methyl-2-oxopyridine thus obtained had a m.p. of 232240 C. andwas sufficiently pure for further use. Recrystallization from propanolgave material of m.p.2422 45 C.

Freshly distilled phosphorus tribromide (69ml.) was added carefully to asuspension of 3-(4-chlorophenyl)-l,Z-dihydro- 6-methyl-2-oxopyridine(30g.) in dimethylformamide (ml.). A solution was obtained initially,but much solid separated later, and it was difficult to maintainstirring as the flask was warmed by being placed in a bath at C. Avigorous exothermic reaction commenced at about 130 C., and the flaskwas removed from the heating-bath. When the reaction had subsided, themixture was allowed to cool slightly, and was then poured into water1,000ml.) containing sufficient ammonia to maintain alkalinity. Themixture was stirred for 30 minutes, and was then extracted withchloroform. The extracts were shaken with decolorizing carbon, filtered,and washed in turn with water, dilute hydrochloric acid, dilute sodiumbicarbonate solution, and water. The chloroform was dried over sodiumsulphate, and evaporated down to leave a low melting solid. This wasredissolved in ether and passed through a column of alumina to removemost of the color. Evaporation of the ethereal eluate yielded 2-bromo-3-(4-chlorophenyl)-6-methylpyridine, m.p.9495 C. This wassufficiently pure for further use, but crystallization from petrol(b.p.6080 C.) raised the m.p. to 9697 C.

EXAMPLE 8 Dimethyl 3-(4-chlorophenyl)-2-methoxypyrid-6-ylmalonate (3.5g)was boiled under reflux for 1 hour with methanolic 2N-potassiumhydroxide (35ml. Water (ca. 50ml.) was added, and most of the methanolwas distilled off under reduced pressure. The remaining aqueous solutionwas washed twice with ether, shaken with decolorizing carbon, filtered,and acidified with acetic acid at a temperature below 15 C. Theprecipitated 3-(4-chlorophenyl)-2-methoxy-pyrid- 6-ylacetic aciddecomposed at 9798 C.

The above acid was converted into its sodium salt by exactneutralization with sodium bicarbonate in aqueous medium. The solutionin water was treated with decolorizing carbon, filtered, and evaporatedto dryness. The crude salt was dissolved in a minimum of ethanol,filtered, and diluted carefully with dry ether to cause the slowprecipitation of sodium 3-(4- chlorophenyl)-2-methoxypyrid-6-ylacetatewhich decomposed at 236238 C.

EXAMPLE 9 Dimethyl 3-(4-chlorophenyl)-2-methoxpyrid-6'ylmalonate (3.0g.)was stirred for 1 hour with sodium hydride (0.41g.; 50 percentdispersion, washed to remove oil) in dry dimethylformamide (25ml.).Methyl iodide (2.5ml.) was added, and gave a mild exothermic reaction.The mixture was stirred at 3540 C. for 1 hour, then diluted with water(ca. 30ml.), and warmed under reduced pressure to remove excess ofmethyl iodide. The solid present was extracted into ether, which waswashed three times with water, dried over sodium sulphate, andevaporated to dryness. Crystallization of the residue from methanol, inthe presence of carbon, yielded colorless prisms of dimethyla-[3-(4-chlorophenyl)-2-methoxypyrid-6-yl]-amethylmalonate, m.p. 106-l07 C.

- tained EXAMPLE A mixture of sodium hydride (l6.8g., 50 percentdispersion in oil washed before use), dimethyl carbonate (90ml.), and5-(4-chlorophenyl)-2-methylpyridine 14.25g.) was stirred under nitrogenfor 18 hours in an oil-bath at lO5-1 C. The reaction mass was cooled,treated with methanol to destroy sodium hydride, and then treated withwater. The solid present was extracted into ether, and the etherealsolution was washed repeatedly with aqueous N-hydrochloric acid untilstarting material had been removed. Further washing with aqueous sodiumcarbonate and with water was carried out, and the solution was driedover sodium sulphate and evaporated down to leave a crude solid. Thiswas redissolved in dry ether (ca. 35ml), and ethanolic hydrogen chloridewas added until no more precipitation took place. The hydrochloride was'collected by filtration, and reconverted to base by treatment withdilute aqueous potassium hydroxide in the presence of ether. Evaporationof the dried ethereal extract gave dimethyl5-(4-chlorophenyl)pyrid-2-ylmalonate which, after crystallization'frommethanol, had m.p. 8586 C.

Diethyl 5-(4-chlorophenyl)pyrid-2-ylmalonate was obtained by a similarprocedure in which diethyl carbonate was used instead of dimethylcarbonate, and the reaction was carried out at 135 C. for 5 hours. Theproduct melted at 4445. 5 C. after crystallization from petroleum ether(b.p.40-60 C.).

The 5-(4-chlorophenyl)-2-methylpyridine used in these preparations wasobtained by treating 2-bromo-3-(4- chlorophenyl) -methylpyridine inacetic acid solution with powdered zinc. Filtration of the reactionmixture, followed by neutralization to faint turbidity with aqueoussodium hydroxide, and extraction with ether, led to the isolation of5-(4- chlorophenyl)-2-methylpyridine, which was crystallized frompetroleum ether (b.p.6080 C.) and had m.p.87-88 C.

EXAMPLE 1 1 By proceeding as in Example 8, but using dimethyl 5-(4-chlorophenyl)pyridZ-ylmalonate instead of dimethyl 3-(4-chlorophenyl)-2-methoxypyrid-6-ylalonate, there was ob-5-(4chlorophenyl)pyrid-Z-ylacetic acid as a hemihydrate which meltedwith decomposition at 102l03 C., and also its sodium salt which waspurified by precipitation from methanolic solution by addition of ether.It decomposed at 260-262 C.

EXAMPLE 12 By proceeding as in Example 9, but using dimethyl 5(4-chlorophenyl)pyrid-2-ylmalonate .instead of dimethyl 3-(4-chlorophenyl)-2-methoxypyrid-6-ylmalonate, there was obtained dimethyla-[5-(4-chlorophenyl)pyrid-2-yl]-a-methylmalonate. This was purified byway of its hydrochloride, isolated from ethereal solution of the crudebase, followed by reconversion to the base, and crystallization frompetroleum ether (b.p.60-80 C.); m.p.58.5-60 C.

EXAMPLE 13 By proceeding as in Example 8, but using dimethyl a-[5-(4-chlorophenyl)pyrid-2yl]-a-methylmalonate instead of dimethyl3-(4-chlorophenyl)2-methoxypyrid-6-ylmalonate, there was obtained sodiuma-[5-(4-chlorophenyl)-pyrid-2- yl )propionate. It was purified byprecipitation from methanolic solution .by addition of ether, and itdecomposed at about 300 C.

By a similar procedure, starting from dimethyl a-[3-(4-chlorophenyl)-2-methoxypyrid-6-yl]-a-methylmalonate (see Example 9),there was obtained sodiuma-[3-(4-chlorophenyl)-2-methoxypyrid-6-yl]proprionate, which decomposedat 276-277 c. I

EXAMPLE 14 6-(4-Bromophenyl)-3-cyanomethyl-2-methylpyridine (4.0g) andaqueous SN-hydrochloric acid (40ml.) were boiled together under refluxfor 4 hours. The solid which has separated was collected by filtrationof the cooled suspension, and it was extracted with aqueous 2N-potassiumhydroxide. The alkaline extract was treated with hydrochloric acid togive a pH of 4. The resulting precipitate was collected by filtration,and washed with water. Crystallisation from ethyl acetate gave6-(4-bromophenyl)-2-methylpyrid-3-ylacetic acid, m.p. l88l89 C.(decomp.).

In a similar fashion, but using 3-cyanomethyl-6-(2,4- dichlorophenyl)-2-methylpyridine instead of 6-( 4-bromophenyl)-3-cyanomethyl-Z-methylpyridine, there was obtained6-(2,4-dichlorophenyl)-2-methylpyrid-3-ylacetic acid, m.p. l92-l93 C.(decomp.); crystallized from ethyl acetate.

The 6-(4-bromophenyl)-3-cyanomethyl-2-methylpyridine (m.p.l l5- C.;crystallized from carbon tetrachloride) used as starting material wasobtained by proceeding as in Example 6 but using6-(4-bromophenyl)-3-chloromethyl-2- methylpyridine in place of3-ch1oromethyl-5-(4-chlorophenyl)-2-methylpyridine. In a similarfashion, from the appropriate chloromethyl compound, there was obtained3- cyanomethyl-6-(2,4-dichlorophenyl)-2-methylpyridine, which wascrystallized from petroleum ether (b.p.80100 C.) and had a m.p. of104l06 C.

The chloromethyl derivatives used above were obtained by processesanalogous to those described in Examples 1 and 6. The following newintermediates were prepared in these syntheses:

Ethyl 6-(4-bromophenyl)-2-methylpyridine-3-carboxylate, m.p.546 C.;crystallized from petroleum ether (b.p.40-60 C.).

Ethyl 6-(2,4-dichlorophenyl)-2-methylpyridine-3 carboxylate, m.p.7374C.; crystallized from ethanol/water mixture.

6-(4-Bromophenyl)-3-hydroxymethyl-2-methylpyridine,

m.p. l30l3l C.; crystallized from carbon tetrachloride.

6-(2,4-Dichlorophenyl)-3-hydroxymethyl-2-methylpyridine, m.p.l l4l l5C.; crystallized from carbon tetrachloride. i,

6-(4-Bromophenyl)-3-chloromethyl-2-methylpyridine,

m.p.99-OO C.; crystallized from cyclohexane.

3-Chloromethyl-6-(2,4-dichlorophenyl)-2-methylpyridine, m.p.867 C.;crystallized from petroleum ether (b.p.60-80 C.).

EXAMPLE l5 6-(4-Bromophenyl)-3-cyanomethyl-2-methylpyridine (0.5g.) anda 10 percent solution of potassium hydroxide in 4:1 ethanol: water(5ml.) were boiled under reflux for 10 minutes. The crystals whichformed were collected by filtration in the cold, and washed well withwater to give 6-(4- bromophenyl )-2-methylpyrid-3-ylacetamide, which wascrystallized from ethanol and had a m.p. of 225-226 C.

EXAMPLE 1 6 A solution of 2-(4-chlorophenyl)-5-cyanomethylpyridine(0.75g.) in SN-hydrochloric acid (l5ml.) was refluxed for 4 hours, thencooled in ice and adjusted to pH 9-10 with aqueous sodium hydroxidesolution (18N). The alkaline solution was washed with two portions ofether, then acidified with glacial acetic acid to pH #5; the whitecrystalline solid was filtered off, washed thoroughly with distilledwater and dried in vacuo. There was thus obtained2-(4-chlorophenyl)pyrid-5- ylacetic acid, which on recrystallizationfrom isopropanol had m.p. 158-l60 C.

The 2-(4-chlorophenyl)-5-cyanomethylpyridine used as starting materialwas obtained as follows:

A solution of ethyl fonnate (60g.) and 4- chloroacetophenoe (124g) inanhydrous toluene (200ml.) was added dropwise to a vigorously stirredsuspension of sodium hydride (50 percent dispersion; 39.2g.) in toluene(800ml.) containing methanol (20ml.) so that a temperature of l-20 C.was maintained. After 4 hours, the thick yellow suspension was treateddropwise with a solution of cyanoacetamide (80g. in water (700ml) sothat the temperature rose to 30 C. The deep red aqueous layer wasseparated, washed once with light petroleum, and heated to reflux withstirring. Distillation was continued until the temperature rose to 95C., a further portion of cyanoacetamide (20g.) was added and the wholerefluxed for 2 hours. After acidification with glacial acetic acid(60ml.), the yellow solid was collected by filtration, washed well withdistilled water, and then stirred with portions of acetone to removecolored contaminants. There was thus obtained 6-(4-chlorophenyl)-3-cyano-2-pyridone which was suitable for use in subsequent stages. Ananalytical sample had m.p.325-329 C. (crystallized from acetic aciddimethyl formamide).

Methanol (50ml.) was added cautiously to a solution of 6-(4-chlorophenyl)-3-cyano-2-pyridone (5g.) in concentrated sulphuric acid(50ml.) so that the mixture came to a gentle reflux, and the clearyellow solution was heated for 18 hours on a steam bath. The solutionwas decanted g.) stirring onto ice (500g. and the pale yellow solid wasfiltered off and washed with distilled water. There was thus obtained3-carbomethoxy-6-(4-chlorophenyl)-2-pyridone which was suitable for usewithout purification, and having m.p.242-244 C. when analytically pure(crystallized from methanol dimethyl formamide).

To stirred molten phosphorus oxybromide (6g.) there was added finelyground 3-carbomethoxy-6-(4chlorophenyl)-2- pyridone l g.), and theresultant solution was heated in an oil bath at 120 C. for 15 minutes,during which time there was a vigorous evolution of hydrogen bromide.The resultant dark viscous mixture was added to ice with vigorousstirring, and the resulting yellow solid was collected by filtration andwashed thoroughly with water. The mixture was stirred with methanol(5ml.) until the mild exothermic reaction has ceased, the suspension wascooled in ice water, and the solid product was removed by filtration andwashed with ice-cold methanol. The crude product was dissolved inbenzene and filtered through alumina (Spence, grade 0; g.) to providewhite crystalline homogeneous 2-bromo-3-carbomethoxy-6- (4chlorophenyl)pyridine. An analytical sample (recrystallized frombenzene-light petroleum) had m.p. l45l47 C.

Reduction of 2-bromo-3-carbomethoxy-6-(4-chlorophenylpyridine) wasachieved by addition of sodium borohydride (0.58g.) to a suspension ofthe ester (2.5g.) in ethanoldimethoxyethane (1:1; 50ml.) stirred at roomtemperature. After periods of 4 hours and 8 hours, further portions(0.6g) of sodium borohydride were added, and stirring was maintained fora further 18 hours. The clear solution was diluted with water (200ml.)and the whole extracted thoroughly with ethyl acetate. Evaporation ofsolvent from the dried organic extracts left2-bromo-6-(4-chlorophenyl)-3-hydroxymethylpyridine which was suitablefor use without purification. Recrystallization from benzene-lightpetroleum provided analytically pure material of m.p. 140-l41 C.

Zinc powder 0.75 g.) was added to a solution of 2-bromo-3-hydroxymethyl-6-(4-chlorophenyl)pyridine (0.75g.) in glacial acetic acid(lOml.), and the resulting suspension was stirred for 2 hours in all,with further portions of zinc (0.75g.) being added after 1 hour and 1%hours. The suspension was filtered to remove unreacted zinc, and thelatter was washed well with small portions of glacial acetic acid. Thecombined acid layers were diluted with ice and neutralized with ammoniasolution l8N). The resultant white precipitate was recovered byextraction with ethyl acetate, and purified by filtration throughalumina (l0g.) in ether solution. There was thus obtained 2-(4-chlorophenyl)-5-hydroxy methylpyridine which can be obtained in twocrystalline forms from benzene-light petroleum 14 (b.p.60-80 C.): platesof m.p. 8 5-87 C. (with resolidification and subsequent melting at C.),or needles of m.p.95 C

Thionyl chloride (l.lml.) was added to a solution of 2-(4-chlorophenyl)-5-hydroxymethylpyridine (2.2g.) in ethylene dichloride(44ml.), and the mixture was stirred at ambient temperature for 30minutes. The solid left after evaporation of the solvent and excessthionyl chloride was dissolved in water, and the cooled solution wasbasified with ammonia solution (l8N). The precipitated solid wasisolated by extraction with ethyl acetate which afforded2-(4-chlorophenyl)-5- chloromethylpyridine which was suitable for use inthe next stage. Recrystallization from light petroleum (b.p.60-80 C.)provided an analytical sample, m.p. 8284 C. A solution of2-(4-chlorophenyl)-5-chloromethyl-pyridine (2.25g.) in anhydrousmethanol (22.5ml) was heated under reflux with sodium cyanide (1.4g.)for 4 hours, and then added to water (ml) and the whole extracted withthree port e f q xlecs at Thswm insqszqra s asw sh with sodium chloridesolution, dried over magnesium sulphate, and then concentrated in vacuoto yield a brown solid which was redissolved in ether and filteredthrough alumina (Spence, grade 0; 42g). 2-(4-Chlorophenyl)-5-cyanomethylpyridine was obtained as a white crystalline solid. Ananalytical sample had m.p.l19-l20C. [crystallized from benzene-lightpetroleum (60-80C.)].

EXAMPLE 17 A solution of 4-(4-chlorophenyl)-2-cyanomethyl-pyridine(2.8g.) in SN-hydrochloric acid (55ml.) was heated under reflux for 6hours. The mixture was cooled in ice and made alkaline with l8N-aqueoussodium hydroxide solution. The solution was washed twice with ether, andthen cooled to 0-5 C. and made acid with glacial acetic acid. The solidprecipitate was filtered off, washed thoroughly with water, and dried invacuo.

4-(4-Chlorophenyl)pyrid-2-ylacetic acid, m.p. l0l-l03 C. (d), thusobtained was converted into the sodium salt by addition to a solution ofsodium bicarbonate (0.51 g.) in water (20ml.). Evaporation of the clearsolution obtained after 1 hour at room temperature provided hydratedsodium 4-(4- chlorophenyl )pyrid-Z-yl-acetic acid.

The 4-(4-chlor0phenyl)-2-cyanomethylpyridine used as starting materialwas obtained as follows:

Acetone (22.8ml.) and 4-chl0r0-w-cyan0 acetophenone (51.6g.) were addedto polyphosphoric acid (588g), and the mixture was stirred firstly atroom temperature for 5 minutes, then on steam bath for 30 minutes. Afterthe addition of a further portion of acetone (22.8ml. the mixture wasraised to l35140 C. in a preheated oil bath, and stirred for 30 minutes.The thick brown mixture was poured slowly into a well-stirred mixture ofwater (21.), l8N-ammonia solution (972ml.), and l8N-aqueous sodiumhydroxide (80ml.) cooled externally so that the temperature was held at5060 C. When addition was complete, the solution was cooled to roomtemperature and the solid which precipitated was filtered, washed wellwith water, then redissolved in chloroform (2.41.). The organic solutionwas washed with water, dried over magnesium sulphate, and concentratedunder reduced pressure. The residual solid wastriturated with ice-cooledether (360ml.), and the resulting solid was collected by filtration.4-(4-Chlorophenyl)-6-methyl-2-pyridone thus obtained was used withoutfurther purification for the next stage. An analytical sample hadm.p.2l9-220 C. (crystallized from methanol).

Redistilled phosphorus tribromide (92ml.) was added over 20 minutes to avigorously-stirred suspension of 4-(4- chlorophenyl)-6-methyl-2-pyridone(20g) in anhydrous dimethylformamide (l26ml.). When the resultingexothermic reaction had ceased, the mixture was placed in an oil bathpreheated to 180 C., and heated until a vigorous reaction, withevolution of hydrogen bromide had set in. Heating was main tained for 30minutes after the vigorous reaction had ceased, and the hot dark mixturewas then poured quickly onto a wellstirred solution of concentratedammonia solution (l8N) in ice-water 1.81.). The mixture was extractedthoroughly with six portions of chloroform, and the combined extractswere successively washed with hydrochloric acid lN, 3x300 ml.), water,and saturated sodium bicarbonate solution. The chloroform solution wasthen dried and the solvent evaporated. The solid residue was dissolvedin ether (100ml.) and filtered through a column of alumina (Spence,grade 300g). Continued elution with this solvent, followed byevaporation of the solvent, provided 2-bromo-4-(4-chlorophenyl)-6-methylpyridine. An analytical sample [crystallized fromisopropanol-light petroleum (60-8O C. ]had m.p.8890 C.

A solution of 2-bromo-4-(4-chlorophenyl)-6-methylpyridine 10g.) inglacial acetic acid (50ml.) was cooled in an ice bath to l5-l 6 C. andstirred, and zinc powder g.) was then added in portions. The temperatureof the stirred solution was maintained at l8-20 C. during this addition,then allowed to rise to C. and held, by ice cooling when necessary, atthis temperature for minutes. A further portion of zinc 10g.) was added,and the suspension was stirred for an additional 30 minutes at 25 C.before filtration to remove unreacted zinc, which was washed thoroughlywith chloroform. The combined filtrates were diluted with water, andmade alkaline with aqueous ammonia solution (18N), and the resultantsuspension was thoroughly extracted with chloroform. The solvent wasevaporated under reduced pressure, and the residue was adsorbed ontoalumina (Spence grade 0; 150g.) from ether solution, andchromatographed. Elution, firstly with ether, later with ethylacetate-ether, 1:20, provided 2-methyl-4-(4-chlorophenyl)pyridine. Ananalytical sample, obtained by recrystallization from light petroleum(6080 C. had m.p.69-72 C.

3-Chloroperbenzoic .acid (1.76g.) was added to an icecooled solution of2-methyl-4-(4-chlorophenyl)-pyridine (1.2g) in chloroform (l2ml.) andthe resultant solution was left for 3 days at 0-4 C. After addition ofN-aqueous sodium hydroxide solution (l5ml.), the Z-phase mixture wasstirred vigorously for 15 minutes, and the chloroform layer was thenseparated and washed with further portions of aqueous sodium hydroxide.After evaporation m.p.from the dried chloroform solution,v2-methyl-4-(4-chlorophenyl)pyridine N- oxide was obtained as acrystalline solid suitable for use in the next step. Analytically purematerial had m.p.l()6l 12 C., and was obtained by recrystallization frombenzene-light petroleum (b.p.60-80 C.

Acetic anhydride (73ml.) was added to a solution of 2methyl-4-(4'chlorophenyl)pyridine N-oxide (24g) in benzene (240ml.), andthe mixture was heated under reflux for 1 hour. After evaporation invacuo of the solvent and excess acetic anhydride, the residual crudeoily mixture was dissolved in methanol (240ml) containing potassiumhydroxide (l9g.), and the resultant brown solution was stirred for 1hour at room temperature. The mixture was concentrated under reducedpressure and the residue partitioned between water and ether. There wasthus obtained a dark brown solid from which4-(4-chlorophenyl)-2-hydroxymethylpyridine was obtained byrecrystallization from benzene-light petroleum (b.p.60-80 C.) asoff-white prisms suitable for use in the next step. An analytical samplehad m.p.lO8-109 C.

A suspension of 4-(4-chlorophenyl)-2hydroxy methylpyridine (3.0g.) inethylene dichloride (29ml.) was stirred and thionyl chloride (1.24ml.)was added dropwise. During the course of the ensuing mildly exothermicreaction, complete dissolution was obtained. The solution was thenstirred for 1 hour at room temperature, by which time precipitation of awhite solid was complete. The mixture was filtered, the solid residuesuspended in water, the pH adjusted to 8 with dilute ammonia solution,and the whole thoroughly extracted with chloroform (3 50ml.). Thecombined extracts were dried (magnesium sulphate) and the solventevaporated to give an ofi-white solid (2.6g) which was redissolved inether and filtered through a column of alumina (Spence grade 0'; g).From the clear filtrate there was obtained 2-chloromethyl-4-(4-chlorophenyl)pyridine, which on recrystallization from lightpetroleum (b.p.40-60 C.) had m.p.7476 C.

Finely ground sodium cyanide (3.4g.) was added portionwise to a stirredsolution of 2-chloromethyl-4-(4-chlorophenyl)pyridine (5.5g.) inanhydrous dimethyl sulphoxide (55ml.), the temperature being adjusted to23-25 C. by means of an ice bath. After the initial exothermic phase,the mixture was stirred at room temperature for 1 hour, and then pouredinto water, 250ml.) and extracted thoroughly with three portions ofether. The combined ethereal layers were washed three times with water,and then dried over magnesium sulphate, and concentrated under reducedpressure.

A sample of the solid residue was recrystallized from benzene-lightpetroleum (b.p.6080 C.) and yielded 4-(4-chlorophenyl)-2-cyanomethylpyridine, m.p.68-7 1 C.

EXAMPLE 1 8 Sodium hydride (SOpercent dispersion in mineral oil; 12.0g.)was added to a solution of 2-bromo-4-(4-chlorophenyl)-6-methylpyridine(14. lg.) in redistilled dimethyl carbonate (l00ml.) containing methanol(O.5ml.). The resultant suspension was stirred under reflux, under amercury seal,'for 4 hours. A further 50ml. of dimethyl carbonate wasadded, and reflux maintained for a further 1 hour. The resulting thickpink suspension was added to ice-water l 1.) containing acetic acid(20ml.) and the whole was extracted with four portions of ether (4100ml.). The combined extracts were washed with water, dried overmagnesium sulphate, and then concentrated in Vacuo to a volume of 200ml. The resulting ethereal solution was stirred and treated dropwisewith a saturated solution of hydrogen chloride in ether (l0ml.), and theprecipitated 2-methoxy-4-(4-chloropheny1)-6-methylpyridine hydrochloridewas isolated by filtration, and washed with several portionsvof ether.The combined ethereal filtrate and washings were washed with water, andthe solvent was removed under reduced pressure. The residual oil wasdissolved in benzene (l0Oml.) and the dark solution was extracted withfour portions of hydrochloric acid (7.5N;25ml.; extracts retained seebelow), then washed with water, dried over magnesium sulphate, andconcentrated under reduced pressure. The residual pale brown solid wascrystallized from methanol and gave dimethyl6-bromo'4-(4-chlorophenyl)pyrid-2-ylmalonate, m.p.l l8-l 20 C.

The combined hydrochloric acid extracts were basified with aqueousammonia solution (18N) under strong cooling, and the whole wasextractedwith several portions of ether. The solvent was evaporated from thecombined ether extracts, and the residue was adsorbed on to florisil(l35g.) from benzene, and then chromatographed. Elution with benzeneremoved traces of by-products, and continued elution with ethylacetate-benzene (successively lpercent and 2 percent) yielded dimethyl6-methoxy-4-(4-chlorophenyl)-pyrid-2-ylmalonate, m.p.l 12-113 C.[crystallized from light petroleum (b.p.6080 C.)

EXAMPLE l9 Sodium hydride (0.247g.) was added to a solution of dimethyl4-(4-chlorophenyl)-6-methoxypyrid-2-ylmalonate (see Example 18; 1.5g.)in anhydrous dimethyl formamide l5ml.). The mixture was stirred in anatmosphere of nitrogen until evolution of hydrogen had ceased andcomplete dissolution had been attained. The clear solution was thentreated with methyl iodide (0.9l5g.) and stirred for a further hour atroom temperature. The yellow suspension was poured into water (l50ml.)and extracted with three portions of ethyl acetate. The combined organicextracts were washed with water, dried over magnesium sulphate, andconcentrated under reduced pressure to a yellow solid. The solid wasdissolved as far as possible in other and the mixture was filteredadjusted to pH with glacial acetic acid, and the whole was extractedwith ethyl acetate. The extract was dried, and the solvent wasevaporated. The residue was rapidly triturated with light petroleum(b.p.40-60 C.) and the resulting mix-' turefiltered to givea-[4-(4-chl0rophenyl)-6-methoXypyrid-2 2-yl]propi0nic acid, m.p.84-87 C.(decomp.).

Esterification of a small sample of this acid with diazomethane affordedthe methyl ester, m.p.65-67. C. [crystallized from light petroleum (4060C. )1.

EXAMPLE 21 EXAMPLE 22 A solution of methyla-[2-(4-chlorophenyl)-6-methylpyrid- 5-yl]-a-cyanopropionate (6g.) -in 5N-hydrochloric acid (60ml.) was refluxed for 6 hours. The solution wascooled, basified .with aqueous'sodium hydroxide, washed with twoportions of ether, and then solidified with glacial acetic acid.

The precipitated acid was filtered off, washed well with distilledwater, and dried in.vacuo. Crystallization of the solid from benzeneprovided large prisms of a-[6-(4-chlorophenyl)-2-methylpyrid-3-yl]-propionic acid, which was heated for 4 hours at 110C. to remove benzene of crystallization, and

. leave unsolvated acid ofm.p. 164- l66 C.

The methyl a-[2-(4chlorophenyl)-6-methylpyrid-5-yl]-acyanopropionateused as starting material was obtained as follows: Sodium hydride (50percent dispersion, 1.4g.) was added to a solution of2(4-chlorophenyl)5-cyanomethyl-6-methylpyridine (6.06g.) in dimethylcarbonate (60ml.) containing methanol (0. lml. and the resultingsuspension was stirred at room temperature for 3 hours. The resultingthick suspension was diluted with anhydrous ether (60ml.), and themixture was filtered and the solid residue washed with several portionsof ether. The solid was the crude oz-sodium derivative of methyl a-[ 2-(4-chlorophenyl )-6-methylpyrid-5-yl ]-acyanoacetate. Acidification of asample of the solid with glacial acetic acid gave methyla-[2-(4-chlorophenyl)-6-methylpyrid-5-yll-a-cyanoacetate, m.p.8 l-83 C.,fine needles,'and 87-90 C., large prisms [crystallized frombenzene-light petroleum (b.p.60-80- C.)].

The crude sodium derivative (ca. 6 g.) was dissolved in dimethoxyethane(60ml), methyl iodide (2.5ml.) was added,

further portions of ether. The combined ethereal solution and extractswere dried, and the solvent evaporated, to give methyla-[2-(4-chlorophenyl)-6-methylpyrid-5-yl]-acyanopropionate suitable foruse without purification. Recrystallization from benzene-light petroleum(b.p.60-80 C.) provided an analytically pure sample of m.p.l00l0l C.

EXAMPLE 23 A solution of triethylamine (2.07g.) and6-(4-chlorophenyl)-2-methylpyrid-3-ylacetic acid (5.3g; Example 2) inethanol (74 o.p.; 125ml.) was shaken with 5 percent palladium oncharcoal catalyst 0.5g.) in an atmosphere of hydrogen until absorptionhad ceased (approximately Hhours). The mixture was filtered to removecatalyst, and the filtrate was evaporated under reduced pressure. Theresidue was stirred with'distilled water and the resulting precipitatewas isolated by filtration and washed well with distilled water. Therewas thus obtained 2-me'thyl o-phenylpyrid3-ylace'tic m.p. l38-139 C.(crystallized from benzene).

Example 24 2-(4-Chrlorophenyl)-4-cyanomethylpyridine (7.05g.) wasdissolved in hot SN-hydrochloric acid (ml.), and the resulting solutionwas heated under reflux for 4%hours. The mixture was then well cooledand adjusted to pH 10-] l with l8N-sodium hydroxide solution. Theresulting aqueous solution was extracted once with ether (SOmL), andthen adjusted to pH 4 with glacial acetic acid. The resulting whiteprecipitate was filtered off, and washed well with distilled water, anddried. The solid (0. lg.) was dissolved as much as possible in acetone(0.5ml.), the mixture was filtered, and to the filtrate was addedpetroleum ether (b.p.60-80 C.; 2.5ml.)'while the mixture was cooled to20 C. The resulting mixture was filtered to give 2-(4-chlorophenyl)pyrid-4-ylacetic acid, 'rn.p. l 00l 02 C. (decomp.). This acid (4.08g.)was added portionwise at room temperature to a vigorously stirredsolution of sodium bicarbonate (l.37g.) in water (40ml.) and acetone(l0ml.), and the clear solution thus obtained was evaporated in vacuo togive sodium 2-(4-chlorophenyl)-pyrid-4-ylacetate monohydrate, m.p. over300 C. (crystallised from acetonewater). t

The 2-(4-chlorophenyl)-4-cyanomethylpyridine used as starting materialwas obtained as follows:

A solution of 4-chlorobromobenzene (192g) in tetrahydrofuran (SOOmL) wasadded dropwise to a vigorously stirred suspension of magnesium turnings(24g) in tetrahydrofuran 150ml.) so that the temperature remained at3540 C. (cooling with ice water was required). When formation of4-chlorophenylmagnesium bromide was complete, finely ground 4-picolineN-oxide (109g) was added portionwise at such a rate as to hold thetemperature at 40 45 C. When addition was complete, the resulting darkred solution was heated a further l /hours at this temperature. Thesolution was then cooled to l520 C. and vigorously stirred while a coldsolution of ammonium chloride (100g) in water (450ml.) and saturatedaqueous sodium chloride solution (250ml.) was added at such a rate thatthe temperature did not rise above 25 C. Ether (500ml) and ethyl acetate(250ml.) were'then added. The organic layer was separated,

and the aqueous layer was extracted with ether-ethyl acetate moniumhydroxide solution. The oily solid thus liberated was and the solutionwas stirred at room temperature for 18 hours.

After evaporation of solvent under reduced pressure;v the residue waspartitioned between water and ether, the organic extracted with ether,and the ethereal extracts were concentrated and filtered through alumina(Spence grade 0; 1kg.). The solvent was evaporated from the filtrate andthere was thus obtained 2-(4-chlorophenyl)-4-methylpyridine, m.p.624 C.[crystallized from light petroleum 4060 acid, I

Sodium hydride (0.04g.; 50 percent dispersion in mineral oil) was addedto a solution of ethyl oxalate (5.88ml.) and 2-(4-chlorophenyl)-4-methylpyridine (5.075g.) in anhydrousdimethylformamide (50ml.) held at 105 C. under nitrogen, and the mixturewas stirred vigorously untilreaction com menced (approximately 5minutes). The brown suspension was cooled as quickly as possible to 70C., and sodium hydride (l.7g.) was added portionwise over 10 minutes tomaintain a steady effervescence. Stirring was continued until hydrogenevolution had ceased (10 minutes), and the brown solution was thendecanted with stirring on to ice-water (250ml.) containing acetic acid(l.5ml.). Ethyl 3-[2-(4- chlorophenyl)pyrid-4-yl]pyruvate was thusobtained as a yellow solid which was isolated by filtration, washedthoroughly with water, and used without further purification. An analytical sample, obtained by recrystallization from benzene-light petroleum(b.p.6080 C.), had m.p.l30-132 C. Crude ethyl3-[2-(4-chlorophenyl)-pyrid-4-yl]pyruvate (ca. 7g.) was heated underreflux with sodium acetate (3g) and hydroxylamine hydrochloride (1.54g.)in ethanol (50ml.) for 40 minutes. Potassium hydroxide pellets (5g.) andwater 10ml.) were then added cautiously, and the reflux was continuedfor a further 30 minutes. The deep red solution was concentrated invacuo, and the residual oil was dissolved in water (lOml.), and thencooled and acidified with glacial acetic acid to pH4-5. The mixture wasfiltered and the sticky solid residue was stirred with a mixture ofmethanol (ml.) and benzene (50ml) to yield the oxime of 3-[2-(4-chlorophenyl)pyrid'4- yllpyruvic acid (5g.) as an off-white solid.This oxime was added over 5 minutes to stirred acetic anhydride (35'mL)heated on a steam bath. The deep red solution was heated for a furtherminutes until evolution of carbon dioxide had ceased, and thenconcentrated in vacuo. The residual oil was dissolved in ether, andwashed with saturated aqueous sodium bicarbonate. The ethereal solutionwas concentrated in vacuo and the deep red solution filtered throughalumina (lOOg.; Spence, grade 0). Continued elution was ether providedpure 2-(4-chlorophenyl)-4-cyanomethyl pyridine, m.p.85-87 C.[crystallized from benzene-light petroleum (b.p.6080 C.)].

EXAMPLE 2-(4-Chlorophenyl)-4-cyanomethylpyridine (6g) was dissolved inmethanol (ml.) containing concentrated sulphuric acid (9.3ml.), and thepale yellow solution was refluxed for 24 hours. The solution was addedto ice (150g), the pH was adjusted to 8 with aqueous ammonia (l8N;l9ml.), and the desired ester was isolated by ether extraction.Evaporation of the solvent and crystallization of the residue frompetroleum ether (b.p.4()60 C.) gave methyl 2-(4chlorophenyl)pyrid4-ylacetate, m.p.4849 C.

EXAMPLE 26 2 4-Chlorophenyl )-4-(a-cyanoisopropyl )pyridine 1.4g.) washydrolyzed by treatment with SN-hydrochloric acid by the methoddescribed in Example 24 to givea-[2'(4-chlorophenyl)pyrid-4-yl]isobutyric acid. A sample of this acid(0.58g.) was added slowly to a well-stirred solution of excessdiazomethane in ether (50ml.) over 10 minutes with ice cooling. Whenevolution of nitrogen had ceased, the solvent was removed in vacuo toyield methyl a-[2-(4-chlorophenyl)pyrid-4-yl1isobutyrate, m.p.7l-72 C.[crystallized from light petroleum (60 C.)]

p The 2-( 4-c hlorophenyl )-4-(a-cyanoisopropyl )-pyridine used asstarting material was obtained as follows:

2- (4-Chlorophenyl)-4-cyanomethylpyridine (5.75g.) was added to asolution of sodamide [obtained from sodium (O. 595 g.) in liquid ammonia(240ml.)]andithe suspension was stirred until a clear green solution wasobtained. Methyl iodide (4.7ml.) was added in one portion, and thesolution was stirred for 30 minutes. After evaporation of all ammonia,the residual solid was partitioned between ether and saturated aqueoussodium chloride solution. The organic phase was separated and theaqueous phase was extracted with two further portions of ether. Thecombined ethereal extract and washings were evaporated to give a mixtureof nitriles (5g.) which was separated by chromatography on alumina(Woelm grade 1, neutral; 200g.). Elution with benzene gave a solidfraction (1.7g.) which when recrystallized from benzene-light petroleum(b.p.6080 C.) gave 2-(4-chlorophenyl)-4-( acyanoisopropyl)pyridine,m.p.9496 C.

EXAMPLE 27 Methyl a-[2-(4-chlorophenyl)pyrid-4-yl1-0:- cyanopropionate'(1.42g.) was hydrolyzed using 5N- hydrochloric acid by a similar methodto that described in Example 22, after which the product was convertedinto the sodium salt by treatment with sodium bicarbonate. There wasthus obtained sodium a-[2-(4-chlorophenyl)pyrid-4-yl]propionate(crystallized from isopropanol The a-cyano compound used as startingmaterial was obtained as follows:

A suspension of sodium hydride (50 percent dispersion; 0.55g.) indimethyl carbonate (23ml) containing 2-(4- chlorophenyl)-4-cyanomethylpyridine 2 .285 g. and methanol (0.1ml.) was stirred atroom temperature. After 20 minutes, a vigorous exothermic reaction setin, and solution became very thick'and pink in color. Stirring wascontinued for a further 40 minutes, after which the mixture wasfiltered.

The solid residue, which was the sodium derivative of methyl a-[2-(4-chlorophenyl )pyrid-4-yl ]-oz-cyanoacelate was washed with severalportions of anhydrous ether, dissolved immediately in dimethoxy ethane(20ml.) and treated at room temperature with methyl iodide (lml.) for 18hours. After evaporation of the solvent in vacuo, the residue waspartitioned between benzene and water, the mixture filtered to removeinsoluble material, and the organic layer then separated. The organiclayer was extracted twice with 2N- hydrochloric acid (10ml. each time),and then with three portions of SN-hydrochloric acid (30ml, 10ml,l0ml.). The latter extracts were combined, neutralized with ammonia18N), and the product extracted with benzene (50ml). The solvent wasevaporated and there was thus obtained methyl or- [-2-( 4-chlorophenyl)pyrid-4-yl l-a-cyanopropionate, m.p.98-9 C. [crystallized from benzenelight petroleum (b.p.60-80C.)].

EXAMPLE 28 A suspension of 6-(4-chlorophenyl)-2-methyl pyrid-3- ylaceticacid (1.55g.) and sodium bicarbonate (0.498g.) in lzl water-methanol(l5ml.) was stirred vigorously until effervescence had ceased and aclear solution had been obtained. The solvents were evaporated underreduced pressure, and the sodium salt was dried by adding benzene(25ml.) and then evaporating it; the latter procedure was carried outthree times. The anhydrous white solid was suspended in anhydrousdimethylformamide l5ml.), ethyl bromide lml.) was added. and the mixturewas stirred for 18 hours at room temperature. Water (ml.) was added tothe clear solution, and the whole was extracted with 1:1 ether-lightpetroleum (b.p.40-60 Cs, 3 25ml.). The combined organic layers werewashed with water (2X25ml.), dried over magnesium sulphate, andconcentrated in vacuo to yield ethyl 6-(4-chl0r0phenyl)-2-methylpyrid-3-ylacetate l.64g.). Recrystallization from light petroleum(b.p.40-60 C.) gave fine white needles of m.p.54-5 C.

EXAMPLE 29 6-(4-Chlorophenyl)-2-methylpyrid-3-ylacetic acid (2.09g.) wasadded to a solution of sodium hydrogen carbonate (0.67g.) in water(30ml.), and the mixture was warmed to 40 C. and stirred until the solidhad dissolved. The liquid was clarifiedby filtration in the presence offiltercel, and the filtrate was stirred at ambient temperature duringthe addition of a solution of hydrated aluminum nitrate (0.85g.) inwater (7ml.), and for 1 hour thereafter. The resultant precipitate wascollected by filtration, washed well with water, and dried in vacuo overphosphorus pentoxide to give aluminum 6-(4- chlorophenyl)2-methylpyrid-3-ylacetate, m.p.295297 C. (decomposition).

EXAMPLE 30 A mixture of 6-(4-chlor0phenyl)-2-methylphrid-3-ylacetic acid(100g) and maize starch (300g) was granulated with a sufficient quantityof w/v starch paste. The granules were passed through a 20-mesh screen,and were dried at a temperature not exceeding 50 C. the dried granuleswere blended with magnesium stearate (4g), and then compressed intotablets containing from 50 to 250mg. of active ingredient. There werethus obtained tablets suitable for oral use for therapeutic purposes.

The pyridine derivatives of this invention exhibit anti-inflammatory,analgesic and antipyretic activity and they reduce the concentration offibrinogen and of cholesterol and/or triglycerides in blood; for examplethey exhibit such activity in standard experimental animals (rats ormice), and they may therefore be used in the treatment of man of otherhost needing such activity. On the basis of results in standardexperimental animals we consider that said pyridine derivatives may beused clinically in man in the formulations and at the doses indicatedbelow, depending upon the clinical effect that is desired:

1. Anti-inflammatory effect. One of said pyridine derivatives, forexample a-[6-(4-chlorophenyl)-2-methylpyrid- 3yl]propionic acid, may beadministered orally in the form ofa tablet at a total daily dose of25-500mg. of said derivative per 70kg. man. Alternatively, saidderivative may be administered topically in the form of an ointment orcream containing 2.5-7.5 percent by weight of said derivative, theointment or cream being administered as necessary.

2. Analgesic effect.

Said pyridine derivative may be administered orally in the form of atablet at a total daily dose of 25-500mg. of said derivative per 70kg.man.

3. Antipyretic effect.

Said pyridine derivative may be administered orally in the form of atablet at a total daily dose of 25-500mg. of said derivative per 70kg.man.

4. Reduction of concentration of fibrinogen, cholesterol and/ortriglycerides.

Said pyridine derivative may be administered orally in the form of atablet at a total daily dose of 25-500mg. of said derivative per 70kg.man.

What we claim is:

1. A compound selected from the group consisting of pyridine derivativesof the formula:

wherein X is a member selected from the group consisting ofhydrogen,alkyl of not more than three carbon atoms,alkoxy of not morethan three carbon atoms,chlorine and bromine; Y is a member selectedfrom the group consisting of phenyl,fluorophenyl, chlorophenyl andbromophenyl; R is a member selected from the group consisting ofhydrogen and methyl; R is alkyl of not more than 5 carbon atoms; with aproviso that Y and CR(CO R )2 are linked to non-adjacent carbon atoms ofthe pyridine nucleus; and non-toxic pharmaceutically acceptableacid-addition salts thereof.

2. A compound as claimed in claim 1 wherein X is a member selected fromthe group consisting of hydrogen, methyl, methoxy, chlorine and bromine;Y is a member selected from the group consisting of phenyl,fluorophenyl, chlorophenyl and bromophenyl; R 15 a member selected from

2. A compound as claimed in claim 1 wherein X is a member selected fromthe group consisting of hydrogen, methyl, methoxy, chlorine and bromine;Y is a member selected from the group consisting of phenyl,fluorophenyl, chlorophenyl and bromophenyl; R1 is a member selected fromthe group consisTing of hydrogen and methyl; R2 is a member selectedfrom the group consisting of methyl and ethyl; and Y and CR1(CO2R2)2 arelinked to non-adjacent carbon atoms of the pyridine nucleus; andnon-toxic pharmaceutically-acceptable acid-addition salts thereof.
 3. Acompound as claimed in claim 1 which is dimethyl5-(4-chlorphenyl)pyrid-2-ylmalonate.